angiogenesis in human development jan kitajewski icrc 926, ph 851-4688, email: jkk9 background...
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Angiogenesis in Human Development
Jan Kitajewski
ICRC 926, ph 851-4688, email: jkk9
BACKGROUND READING:
Vascular Development“Signaling Vascular Morphogenesis and Maintenance”Douglas Hanahan. Science 277: 48-50. in Perspectives. (1997)
Notch and arterial specification
“Notch Function in the Vasculature: insights from zebrafish,mouse and man”Carrie Shawber and Jan Kitajewski. BioEssays 3: 225-34 (2004)
Wnts and retinal angiogenesis
“Wnt/Frizzled Signaling in the Vasculature: New Angiogenic Factors in Sight”Nestor Masckauchan and Jan Kitajewski. Physiology 21: 181-188 (2006)
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Vascular Development
• Vasculogenesis = de novo tube formation• Angiogenesis = sprouting of new tubes off of pre-existing
tubes
• Endothelial Cell = cell type that makes up and lines blood vessels
• Mural Cells = specialized cells that surround blood vessels– Pericytes– Smooth muscle cells
• Angiogenic Factors– Vascular Endothelial Growth Factor (VEGF-A, VEGF-B, PlGF, VEGF-
C, VEGF-D– Angiopoietins (Ang 1, Ang2, ………..)– Notch ligands (Jagged1, Delta4)
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1.5 day2.5 day2.0 day
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Nature Biotechnology 22, 595 - 599 (2004)
Chemical suppression of a genetic mutation in a zebrafish model of aortic coarctationRandall T Peterson1, Stanley Y Shaw1, 2, Travis A Peterson1, David J Milan1, Tao P Zhong1, 3, Stuart L Schreiber2, Calum A MacRae1 & Mark C Fishman1, 4
1 Developmental Biology Laboratory, Cardiovascular Research Center, Massachusetts General Hospital
Nature Chemical Biology 1, 263-264 (2005)
High-throughput assay for small molecules that modulate zebrafish embryonic heart rate.Burns CG, David J Milan, Grande DJ, Rottbauer W, Calum A MacRae & Mark C Fishman
Developmental Biology Laboratory, Cardiovascular Research Center, Massachusetts General Hospital
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Angiogenesis - Basement Membrane Breakdown
Smooth MuscleCells
Endothelium
BasementMembrane
Proteases
AngiogenicStimulus(VEGF)
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Angiogenesis - Endothelial Cell Migration
Endothelium
NascentVascular Sprouts
VEGF
Smooth MuscleCells
BasementMembrane
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Angiogenesis - Endothelial Cell Proliferation
Endothelium
VEGF
SproutElongationSmooth Muscle
Cells
BasementMembrane
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Angiogenesis - Capillary Morphogenesis
Endothelium
VEGF
NewLumen
FormationSmooth MuscleCells
BasementMembrane
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Angiogenesis - Vascular Maturation
Endothelium
VEGF
Vascular Pruning(apoptosis?)
SMC, pericyterecruitment
Smooth MuscleCells
BasementMembrane
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Angiogenesis - Vascular Maturation
Endothelium
VEGF
Endothelialcell-cell junctions
Smooth MuscleCells
BasementMembrane
NegativeFeedback
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VEGF and VEGF Receptors
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VEGF-receptor signalingVEGF-receptor signaling
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Vasculogenesis
Lymphangiogenesis
Angiogenesis
Mesoderm formation
Hemangioblasts Blood island formation
Endothelial cells
Hematopoietic cells
Primary vascular plexus
Lymphatics
Lymphangioblasts
VeinsCapillaries
Arteries
VE-CadherinbFGF
VEGF AVEGFR-1/2/3TGFEphrinB2/EphB4Endoglin Notch
Tal1/sclGata 1
Ang1/2Tie2PDGF BId1/3
VEGF C/DVEGFR-3
VEGF AVEGFR-2TGF
Tal1/sclGata 1
Vascular Development
Karkkarnin et al., 2002 Nature Cell Biology
GM-CSF
Notch on Notch off
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Jagged1Notch1Notch2Notch3Notch4
Dll1Dll3Dll4
Endothelium& other tissuesVascular SmoothMuscle CellsEndothelial &Vascular SmoothMuscle Cells
Arterial Endothelium
Mailhos, 2001
Shutter, 2000
Notch/Notch ligands expressed in arterial endothelium
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VEGF-A
Notch1,4 Dll4
Hey1,2
EphB4 ephrinB2
Venous EC
Arterial EC
Arterial/Venous Specification
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Oliver, G., 2004Oliver, G., 2004
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F.Sabin Model of Lymphatic Vasculature F.Sabin Model of Lymphatic Vasculature Development (venous origin)Development (venous origin)
Oliver, G., Oliver, G., 20042004
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VEGF and VEGF Receptors
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Lymphatic Vasculature DevelopmentLymphatic Vasculature Development
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Structure of blood and lymphatic vasculature in dermis
normal + lymphatics - lymphatics
Mouse with mutation in VEGFR-3blood vessel
lymphatic vessel
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Shayan, R. et al. Carcinogenesis 2006 27:1729-1738Shayan, R. et al. Carcinogenesis 2006 27:1729-1738
Molecular characteristics of lymphatic vessel subtypes Molecular characteristics of lymphatic vessel subtypes found in the dermal and subcutaneous layers of normal found in the dermal and subcutaneous layers of normal
mammalian skinmammalian skin
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Harvey and Oliver, Harvey and Oliver, Curr.Opin Genet Dev, 20042004
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QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.
Fruttinger, 2004
Delta4 expressed in retinal vasculature
in situ hybridization
arterial expression tip cell expression
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Normal intraretinal vasculature
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Retinopathy of Prematurity
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Familial Exudative
Vitreoretinopathy • First described by Criswick and Schepens [Am. J. Ophthalmol. 68: 578-594 (1969)]• Autosomal dominant, recessive, and X-linked forms; variable phenotype• Clinical characteristics
mild to severe vision loss retina: avascular peripheral retina, exudates,
neovascularization, fibrovascular masses,traction or rhegmatogenous retinal detachment
vitreous: posterior vitreous detachment, fibrovascular membranes, hemorrhageother: cataract, neovascular glaucoma
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Autosomal dominantFEVR mutationsIn the cysteine-richdomain (CRD) of Fz4
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Retinal defects in FEVR patients heterozygous for Fz4 M157V
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WntFrizzledreceptorDishevelled
GSK-3APCAxinppp
Cadherins
TCF
-catenin cadherin bound
-catenincytosolic-cateninnuclear
Frizzled-4 is a Wnt receptor
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Intraocular hemorrhage in Fz4(-/-) mice
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Absence of intra-retinal capillaries in
Fz4(-/-) mice WT -/-
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Norrie Disease
• First described by Norrie (1927) and analyzed systematically by Mette Warburg [Acta Ophthalmologica 39: 757-772 (1961); 41: 134-146 (1963); 89: 1-147 (1966)]
• X-linked recessive with variable phenotype• Clinical characteristics
moderate vision loss to congenital blindnessretina: retinal folding and detachment, retinaldegeneration, fibrovascualar masses, vitreoretinalhemorrhagevitreous: persistent primary vitreousother: progressive sensorineural deafness
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WntFrizzledreceptorDishevelled
GSK-3APCAxinppp
Cadherins
TCF
-catenin cadherin bound
-catenincytosolic-cateninnuclear
Norrin is a ligand for Frizzled-4
Norrin
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Molecular genetics of Norrie Disease and FEVR
• FEVROne autosomal dominant FEVR gene identified by Robaitaille et al [Nature Genetics 32: 326-330 (2002)] encodes Frizzled4, a putative Wnt receptor. A second autosomal dominant FEVR locus encodes the Wnt co-receptor Lrp5 [Toomes et al [IOVS 45: 2083-2090 (2004)]; Jiao et al [Am J Hum Genet 75: 878-884 (2004)].
• Norrie diseaseGene identified by Berger et al and Chen et al [Nature Genetics 1: 199-203 and 204-208 (1992)]The encoded protein is small (133 amino acids in length), has the same pattern of cysteines as seen in transforming growth factor beta, and begins with a signal sequence (i.e. it looks like a secreted protein). No known biochemical function.
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Vessel component to human disease
• Tumor angiogenesis• Diabetic vascular complication
– Diabetic retinopathy– Stroke– Ischemia– Wound repair
• Heart disease• Obesity• Blindness
– Wet Macular Degeneration– Retinopathy of Prematurity
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Research opportunity
Summer research on tumor angiogenesisat Eisai Pharmaceuticals, Japan
with Dr. Yasuhiro Funahashi